Ovarian follicle development is a dynamic process that requires exquisite regulation of multiple cell types in the ovary in response to locally produced and extragonadal factors at each stage of development. In this competitive renewal of our Program Project we will combine our various expertise's in nuclear receptors, mouse models, ovarian histopathology, neuroendocrine regulation, and signaling into three comprehensive and highly interactive projects to evaluate the mechanisms by which activin, estrogen, and FSH signal to regulate ovarian follicular development. Interruption of the normal signaling by any of these factors results in infertility or subfertility. We will test the hypotheses that activin plays a critical role in normal development of the ovarian follicles, that normal follicular development requires signaling through estrogen receptor alpha that is not dependent on its binding to DNA estrogen response elements, and that FSH-directed signaling via protein kinase A and consequently the phosphatidylinositol 3-kinase pathway simultaneously disengages an inhibitory pathway that restrains granulosa cell differentiation and stimulates differentiation. The research projects and supporting cores are: Project I, Activin Regulation of Ovarian Follicle Development, Drs. Kelly Mayo and Teresa Woodruff;Project II, Nonclassical Estrogen Receptor Alpha Action in the Ovary, Drs. Larry Jameson, Jon Levine and Mary Hunzicker-Dunn;Project III, FSH-Stimulated Signals that Regulate Follicular Maturation, Drs. Mary Hunzicker-Dunn and Larry Jameson;Core A, Administrative Core, Dr. Mary Hunzicker-Dunn;Core B, Ovarian Procurement, Processing and Analysis Core, Dr. Teresa Woodruff. The issues addressed in the Program Project underlie the essence of the regulation of fertility. By our united efforts we will optimize progress on each project to better understand the control follicular development.